ORIGINAL RESEARCH

Outcome Reporting in Cardiac Surgery Trials: Systematic Review and

Critical Appraisal
Michael Goldfarb, MD; Laura Drudi, MD; Mohammad Almohammadi, MD, MPH; Yves Langlois, MD; Nicolas Noiseux, MD;
Louis Perrault, MD; Nicolo Piazza, MD; Jonathan Afilalo, MD, MSc

Background-—There is currently no accepted standard for reporting outcomes following cardiac surgery. The objective of this
paper was to systematically review the literature to evaluate the current use and definition of perioperative outcomes reported in
cardiac surgery trials.
Methods and Results-—We reviewed 5 prominent medical and surgical journals on Medline from January 1, 2010, to June 30,
2014, for randomized controlled trials involving coronary artery bypass grafting and/or valve surgery. We identified 34 trials
meeting inclusion criteria. Sample sizes ranged from 57 to 4752 participants (median 351). Composite end points were used as a
primary outcome in 56% (n=19) of the randomized controlled trials and as a secondary outcome in 12% (n=4). There were 14
different composite end points. Mortality at any time (all-cause and/or cardiovascular) was reported as an individual end point or
as part of a combined end point in 82% (n=28), myocardial infarction was reported in 68% (n=23), and bleeding was reported in 24%
(n=8). Patient-centered outcomes, such as quality of life and functional classification, were reported in 29% (n=10). Definition of
clinical events such as myocardial infarction, stroke, renal failure, and bleeding varied considerably among trials, particularly for
postoperative myocardial infarction and bleeding, for which 8 different definitions were used for each.
Conclusions-—Outcome reporting in the cardiac surgery literature is heterogeneous, and efforts should be made to standardize the
outcomes reported and the definitions used to ascertain them. The development of standardizing outcome reporting is an essential
step toward strengthening the process of evidence-based care in cardiac surgery. ( J Am Heart Assoc. 2015;4:e002204 doi:
10.1161/JAHA.115.002204)
Key Words: cardiac surgery • outcomes • systematic review

O utcome measures vary between trials, particularly in the

field of cardiac surgery, for which there is currently no
widely accepted standard for reporting postoperative adverse
impeded by the heterogeneity of pooled outcomes. Further-
more, generic composite outcomes traditionally used in
cardiology such as major adverse cardiac events (MACE; death,
events. The lack of uniformity has hindered the ability to myocardial infarction [MI] with or without revascularization)
compare and synthesize findings across different trials. Efforts and major adverse cardiovascular and cerebrovascular events,
to perform meta-analyses in cardiac surgery have often been or MACCE (death, MI, stroke), are neither designed nor adapted
for cardiac surgery because they do not reflect other important
postsurgical complications. The Society of Thoracic Surgeons
From the Divisions of Cardiology (M.G., J.A.) and Cardiac Surgery (Y.L.), Jewish
General Hospital, McGill University, Montreal, Quebec, Canada; Division of (STS) has provided definitions of postsurgical complications
Vascular Surgery (L.D.) and Centre for Clinical Epidemiology, Lady Davis and a surgery-specific composite outcome consisting of
Institute (J.A.), McGill University, Montreal, Quebec, Canada; Divisions of in-hospital death, stroke, prolonged ventilation, acute kidney
Medicine (M.A.) and Cardiology (N.P.), McGill University Health Center, McGill
University, Montreal, Quebec, Canada; Division of Cardiac Surgery, Centre
injury, deep sternal wound infection, or reoperation1; however,
Hospitalier de L’Universite de Montreal, Montreal, Quebec, Canada (N.N.); the extent to which this composite outcome has been adopted
Division of Cardiac Surgery, Montreal Heart Institute, Universite de Montreal, for use in clinical trials is unknown. The appropriateness of
Montreal, Quebec, Canada (L.P.).
combining adverse events with differing clinical impacts (eg,
Correspondence to: Jonathan Afilalo, MD, MSc, FACC, FRCPC, Jewish
General Hospital, 3755 Cote Ste Catherine Rd, E-222, Montreal, Quebec,
stroke and wound infection) has also been questioned.2
Canada H3T 1E2. E-mail: jonathan.afi[email protected] There is a pressing need to improve and homogenize
Received June 8, 2015; accepted July 9, 2015. outcome reporting in cardiac surgery, similar to what was
ª 2015 The Authors. Published on behalf of the American Heart Association, successfully achieved in other fields such as the RIFLE
Inc., by Wiley Blackwell. This is an open access article under the terms of the classification3, the Bleeding Academic Research Consortium4
Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is and the Transcatheter Valve Academic Research Consortium
properly cited and is not used for commercial purposes. (VARC).5 The objective of this paper was to review the

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 1

Outcome Reporting in Cardiac Surgery Trials Goldfarb et al

ORIGINAL RESEARCH
selection and definition of individual and composite outcomes resolved by consensus. The primary and secondary outcomes
reported in the recent body of randomized controlled trials in were represented in tabular format and summarized according
cardiac surgery. With this knowledge, stakeholders would be to the number and proportion of randomized controlled trials
better equipped to develop recommendations for standard- reporting each outcome measure. The Stata 13 software
ized outcome reporting adapted to cardiac surgery. package (StataCorp) was used to organize the extracted data
and to prepare summary statistics.

Methods
Results
Search Strategy Of 190 potentially relevant trials, 34 met the selection criteria
The PubMed search string “Cardiac Surgical Procedures” and were included in our systematic review (Figure). Included
(MeSH) AND “Randomized Controlled Trial” (Publication Type) trials were evenly distributed among the journals searched
was used to identify cardiac surgery randomized controlled (Table 1). Sample sizes ranged from 57 to 4752 participants
trials published between January 1, 2010, and June 30, 2014. (median 351; quartiles 1 to 3: 198 to 699). Overall, 26 trials
Our search was limited to 5 high-impact journals in general involved coronary artery bypass grafting only, 5 involved valve
medicine, cardiovascular medicine, and cardiothoracic sur- repair or replacement only, and 3 involved a combination. The
gery6: New England Journal of Medicine, Circulation, Journal of maximum duration of follow-up for outcome surveillance
the American College of Cardiology, Annals of Thoracic ranged from 5 to 14 days (median 7.5 days) in 6 trials, from
Surgery, and The Journal of Thoracic and Cardiovascular 30 days to 1 year (median 365 days) in 19 trials, and was
Surgery. Reference lists from retrieved manuscripts were >1 year (median 1825 days) in 9 trials.
hand searched to supplement the PubMed search. Mortality (all-cause and/or cardiovascular) was reported as
an individual end point or as part of a composite end point in
28 trials (82%), MI was reported in 23 trials (68%), need for
Selection Criteria repeat revascularization or reoperation was reported in 22
Studies were included if the study design was randomized and trials (65%), stroke or transient ischemic attack was reported
the study population was undergoing coronary artery bypass in 18 trials (53%), acute kidney injury was reported in 11 trials
grafting and/or heart valve repair or replacement surgery. (32%), and bleeding complications were reported in 8 trials
Studies were excluded if the primary outcome was not a (24%) (Table 2). Patient-centered outcomes were reported in
clinical event (eg, the primary outcome was a biomarker) or if 10 trials (29%). Health care resource utilization was reported
the study population was pediatric or focused on congenital in 12 trials (35%).
heart disease. Case reports, case series, editorials, reviews, Composite end points were used as the primary outcome
and post hoc analyses of randomized controlled trial data measure in 19 trials and as a secondary outcome measure in 4
were also excluded. trials. Overall, 14 different composite end points were used, of
which 6 were variants of the MACCE composite, 3 were variants
of the MACE composite, and none were based on the STS
Data Extraction composite. Eight of 9 trials using the MACE or MACCE
For each article meeting inclusion criteria, the following composite incorporated repeated revascularization procedures.
variables were extracted: first author, journal, year of publica- The operational definitions of individual end points were
tion, trial name and registration, sample size, study population, equally variable. MI was defined based on World Health
intervention, control, primary outcomes, secondary outcomes, Organization criteria in 2 studies, European Society of Cardi-
and duration of follow-up. In addition, the operational defini- ology and/or American Heart Association criteria in 4 studies,
tions used to ascertain MI, stroke, prolonged ventilation, acute VARC criteria in 1 study, creatinine kinase elevation greater
renal injury, and bleeding were extracted. Patient-centered than the upper limit of normal in 2 studies, creatinine kinase or
outcomes included postoperative pain, quality of life, mood, troponin elevation >3 times the upper limit of normal in 1 study,
neurocognitive function, and New York Heart Association creatinine kinase or troponin elevation >5 times the upper limit
functional class. Health care resource utilization included of normal in 4 studies, and creatinine kinase or troponin rise to
hospital and intensive care unit length of stay and cost analyses. various levels depending on time after surgery in 3 studies. No
diagnostic criteria for MI were provided in 5 trials.
Stroke was defined based on focal neurological deficit with
Analysis imaging findings in 3 trials and on acute focal neurological
Studies were reviewed, and data were extracted in duplicate deficit lasting ≥24 hours with or without confirmatory imaging
by 2 independent observers (M.G., L.D.); disagreements were in 11 trials; no diagnostic criteria were provided in 6 trials.

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 2

Outcome Reporting in Cardiac Surgery Trials Goldfarb et al

ORIGINAL RESEARCH
Figure. Flow diagram for search strategy. CABG indicates coronary artery bypass grafting.

Acute kidney injury was defined based on need for renal the most striking findings was the heterogeneity of composite
replacement therapy in 5 trials, need for renal replacement end point reporting. This was apparent at 3 different levels.
therapy or prespecified elevation in creatinine (each with First, the decision to use or not use a composite as the primary
different thresholds, ranging from 221 mmol/L [2.5 mg/dL] outcome measure was evenly split between trials. Second, the
to 309 mmol/L [3.5 mg/dL]) in 3 trials, and prespecified choice of events included in composites was highly variable.
elevation of twice the preoperative creatinine level with or Third, the operational definitions of events were ill defined,
without oliguria in 2 trials; no diagnostic criteria were provided particularly the thresholds used to dichotomize continuous
in 2 trials. Prolonged ventilation or intubation was defined as metrics such as troponin rise for MI or ventilation duration.
>24 hours in 2 trials and >48 hours in 1 trial. The definition of MACE and MACCE also had varied definitions in the trials,
postoperative bleeding differed in each of the 8 trials in which similar to prior reports in general cardiology.7
it was reported. Heterogeneity in cardiac surgery outcome reporting limits
the ability to synthesize and meta-analyze results across trials
to generate guidelines with the highest level of evidence.8
Discussion This is relevant, given the shift toward evidence-based
To our knowledge, this review of adult cardiac surgery trials is practice derived from randomized controlled trials in cardiac
the first to examine the current state of outcome reporting. We surgery and other surgical subspecialties.9 In addition,
found that mortality and MI were most frequently reported as nonstandardized outcome measures limit the ability to
individual or composite end points and, conversely, that the directly compare the effectiveness of various surgical tech-
STS composite was not used as an outcome measure. One of niques, perioperative interventions, and providers.10 As new

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 3

Outcome Reporting in Cardiac Surgery Trials Goldfarb et al

ORIGINAL RESEARCH
Table 1. Summary of Trials Meeting Inclusion Criteria

Trial Name Journal and

First Author or Identifier Year N Intervention Control Primary Outcomes

Adams et al 201411 NCT01240902 NEJM 2014 795 TAVR SAVR Mortality (1 year)
Morice et al 201312 SYNTAX Circ 2014 1800 CABG PCI Composite: mortality, MI, CVA,
revasc. (5 years)
Chocron et al 201313 MOTIV CABG ATS 2013 361 Escitalopram after Placebo after CABG Composite: mortality, MI, low CO
CABG syndrome, ventilation >24 hours,
reintubation, brain injury, delirium,
AKI, pneumonia, sepsis, DSWI,
heart failure, hospitalization,
reoperation (1 year)
Diegeler et al 201314 GOPCABE NEJM 2013 2539 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA, AKI
requiring dialysis, revasc.
(30 days, 1 year)
Kamalesh VA CARDS JACC 2013 198 PCI CABG Composite: mortality, MI (2 years)
et al 201315
Karkouti et al 201316 NCT00914589 JTCS 2013 409 Recombinant factor XIII Placebo after cardiac Blood transfusions (7 days)
after cardiac surgery surgery
Lamy et al 201317 CORONARY NEJM 2013 4752 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA, AKI
requiring dialysis (30 days);
Composite with revasc. (5 years)
Sezai et al 201318 UMIN000004537 ATS 2013 367 Carperitide during CABG Placebo during Composite: mortality, MI, CVA,
CABG revasc., heart failure,
hospitalization (1 year)
Shi et al 201319 NCT01596738 ATS 2013 120 Tranexamic acid during Placebo during Blood transfusions (perioperative)
CABG CABG
Bokesch et al 201220 CONSERV-2 JTCS 2012 218 Tranexamic acid during Ecallantide during Composite: MI, blood transfusions,
CABG CABG chest tube drainage, creatinine
change (30 days)
Deja et al 201221 — JTCS 2012 390 Aspirin before CABG Placebo before CABG Blood loss and chest tube drainage
(12 hours)
Desai et al 201222 — JTCS 2012 189 Strict glucose control Liberal glucose Composite: mortality, AKI, DSWI,
after CABG control after CABG ventilation >24 hours, pneumonia,
length of stay, AF; time to target
glucose range (30 days)
Farkouh et al 201223 FREEDOM NEJM 2012 1900 PCI CABG Composite: mortality, MI, CVA
(30 days, 1 year)
Houlind et al 201224 DOORS Circ 2012 900 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA
(30 days)
Kang et al 201225 EASE NEJM 2012 57 Early surgery for Usual care for Composite: mortality, clinical
endocarditis endocarditis embolic event (6 weeks)
(<48 hours)
Lemma et al 201226 On-Off JTCS 2012 411 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA, AKI,
ARDS, reoperation for bleeding
(30 days)
Mannacio — ATS 2012 230 IABP for 12 hours before IABP for 2 hours Mortality (in hospital)
et al 201227 CABG before CABG
Sezai et al 201228 UMIN000002489 JTCS 2012 105 Landiolol IV with or No beta blocker after AF (1 week)
without oral bisoprolol CABG
after CABG
Torina et al 201229 — JTCS 2012 60 Modified ultrafiltration Usual care after Blood transfusions, chest tube
after CABG CABG drainage, hospital and critical care
length of stay (48 hours)

Continued

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 4

Outcome Reporting in Cardiac Surgery Trials Goldfarb et al

ORIGINAL RESEARCH
Table 1. Continued

Trial Name Journal and

First Author or Identifier Year N Intervention Control Primary Outcomes

Bonow et al 201130 STITCH NEJM 2011 601 CABG Medical therapy Mortality (1 year)
Feldman et al 201131 EVEREST II NEJM 2011 279 Percutaneous MV repair Surgical MV repair or Composite: mortality, MI, CVA, AKI,
replacement DSWI, ventilation >48 hours,
reoperation GI complication, AF,
sepsis, transfusion ≥2 units
(30 days)
Composite: mortality, reoperation,
severe MR (30 days)
Kourliouros ISRCTN41309956 JTCS 2011 104 Atorvastatin high dose Atorvastatin low- AF (in hospital)
et al 201132 after CABG or SAVR dose after CABG or
SAVR
Mehta et al 201133 PREVENT-IV Circ 2011 1034 Edifoligide before Placebo before Composite: mortality, MI, revasc.
treatment to venous treatment to (5 years)
grafts venous grafts Venous graft failure (1 year)
Sezai et al 201134 NU-HIT for CRF JACC 2011 303 Carperitide during CABG Placebo during AKI (1 year)
CABG
Smith et al 201135 PARTNER NEJM 2011 699 TAVR SAVR Mortality (1 year)
Wimmer-Greinecker NCT00985634 ATS 2011 110 CABG with CABG with Composite: mortality, MI, graft
et al 201136 thermosensitive conventional vessel occlusion, low CO syndrome
polymer loops (30 days)
Grossi et al 201037 RESTOR-MV JACC 2010 165 CABG with ventricular CABG with or Composite: mortality, MI, CVA,
reshaping without MV repair reoperation, device failure
(2 years)
Hueb et al 201038 MASSII Circ 2010 611 CABG or PCI Medical therapy Composite: mortality, MI, revasc.
(10 years); individual end points
Hueb et al 201039 MASSIII Circ 2010 308 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA,
revasc. (5 years)
Kapur et al 201040 CARDia JACC 2010 510 PCI CABG Composite: mortality, MI, CVA
(1 year)
Moller et al 201041 Best Bypass Circ 2010 341 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA,
Surgery cardiac arrest, low CO syndrome,
revasc. (30 days)
Omran et al 201042 — JTCS 2010 220 CABG with ventral CABG AF (in hospital)
cardiac denervation
Veeger et al 201043 CABADAS ATS 2010 726 Aspirin/dipyridamole or Aspirin after CABG Composite: mortality CV, MI, revasc.
warfarin after CABG (14 years)
Weltert et al 201044 — JTCS 2010 320 Erythropoietin before Usual care Blood transfusions (in hospital)
CABG

AF indicates atrial fibrillation; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; ATS, Annals of Thoracic Surgery; CABG, coronary artery bypass grafting; Circ, Circulation;
CO, cardiac output; CVA, cerebrovascular accident; DSWI, deep sternal wound infection; GI, gastrointestinal; IABP, intra-aortic balloon pump; IV, intravenous; JACC, Journal of American
College of Cardiology; JTCS, Journal of Thoracic and Cardiovascular Surgery; MI, myocardial infarction; MR, mitral regurgitation; MV, mitral valve; NEJM, New England Journal of Medicine; PCI,
percutaneous coronary intervention; revasc., repeat revascularization; SAVR, surgical aortic valve replacement; TAVR, transcutaneous aortic valve replacement.

competing techniques and technologies emerge, it is increas- models, most risk scores use mortality as the sole end point,
ingly important that surgical outcome reporting be compara- neglecting the importance of other complications and patient-
ble among trials. Due to the lack of consensus outcome centered outcomes.
measures in cardiac surgery, investigators often default to The use of composite end points in cardiac surgery may be
using mortality as the end point of choice, despite being beneficial for several reasons. Composite end points avoid the
grossly underpowered to do so (as was apparent in the many arbitrary choice of a single outcome when several may be of
of the trials reviewed and in an even greater proportion of clinical importance for the cardiac surgery patient45 and allow
observational studies). Similarly, with the exception of the STS for estimation of the net clinical benefit of the intervention

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 5

Outcome Reporting in Cardiac Surgery Trials Goldfarb et al

ORIGINAL RESEARCH
Table 2. Graphical Representation of Primary and Secondary Outcomes in Included Trials With Overview of Commonly Used
Combined Endpoints in Cardiovascular Research

VARC-2

STS

MACCE

MACE

Reop/ Bleed/ Primary Endpoint

Author/Year MI Mortality Revasc CVA/TIA AKI Transfusion Other Follow-up Duration Resource Utilization*
Adams et al 201411 ○ ● ○ ○ Prosthesis gradients 1 year
Morice et al 201312 ● ● ● ● 1 year
Chocron et al 2013 13
● ● ● ● ● QOL, depression 1 year
Diegeler et al 201314 ● ● ● ● ● ○ 1 year Hosp+ICU LOS
Kamalesh et al 201315 ● ● ○ ○ 2 years
Karkouti et al 201316 ○ ○ 7 days
Lamy et al 201317 ● ● ● ● ● QOL, Neurocognitive 1 year
Sezai et al 201318 ● ● ● ● Heart failure 2 year Hosp LOS
Shi et al 2013 19
○ ● 1 year Hosp+ICU LOS
Bokesch et al 201220 ○ ○ ○ ○ ● Neuro dysfunction 12 hours
Deja et al 201221 ○ ○ ○ ● Chest tube drainage 12 hours
Desai et al 2012 22
● ● Atrial fibrillation, DSW 30 days ICU LOS
Farkouh et al 201223 ● ● ○ ● 30 days
Houlind et al 201224 ● ● ● ● QOL 30 days Hosp+ICU LOS
Kang et al 2012 25
● Embolism, repeat hosp 6 months
Lemma et al 201226 ● ● ● ● ● ARDS 30 days Hosp+ICU LOS
Mannacio et al 201227 ● ○ ○ Hospitalization Hosp+ICU LOS
Sezai et al 2012 28
○ ○ ○ Atrial fibrillation 1 year
Torina et al 201229 ● 48 hours Hosp+ICU LOS
Bonow et al 201130 ● Repeat hosp 1 year
Feldman et al 201131 ● ● ● ● ● ● QOL, NYHA class 1 year
Kourliouros et al 201132 Atrial fibrillation Hospitalization
Mehta et al 201133 • ● ● Graft closure 5 years
Sezai et al 201134 ○ ○ ○ ● ○ Biomarkers 1 year
Smith et al 201135 ○ ● ○ ○ ○ NYHA class 1 year Hosp+ICU LOS
Wimmer-Greinecker ● ● ○ Graft occlusion 30 days
et al 201136
Grossi et al 201037 ● ● ● ● NYHA class 2 years
Hueb et al 201038 ● ● ● ○ Angina 10 years
Hueb et al 201039 ● ● ● ● Angina 5 years
Kapur et al 2010 40
● ● ○ ● NYHA class 1 years
Moller et al 201041 ● ● ● ● 30 days Hosp+ICU LOS
Omran et al 201042 Atrial fibrillation 30 days Hosp LOS
Veeger et al 2010 43
● ● ● 14 years
Weltert et al 201044 ● Hospitalization Hosp+ICU LOS

● Solid circle indicates primary outcomes. ○ Open circle indicates secondary outcomes. Composite outcomes are categorized based on their individual components. VARC-2 also
incorporates vascular complications, arrhythmias and other outcome measures. STS composite morbidity score also incorporates prolonged ventilation greater than 24 hours and deep
sternal wound infection. MACE and MACCE have variable definitions (see Kip et al JACC 2008). AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; CVA, cerebrovascular
accident; DSW, deep sternal wound infection; Hosp, hospital; LOS, length of stay; ICU, intensive care unit; MACCE, major adverse cardiovascular and cerebrovascular events; MACE, major
adverse cardiovascular events; MI, myocardial infarction; NYHA, New York Heart Association; Reop, reoperation; Revasc, revascularization; TIA, transient ischemic attack; QOL, quality of
life; STS, Society of Thoracic Surgeons; VARC-2, Valve Academic Research Consortium.
*Resource Utilization includes ICU length of stay, hospital length of stay, testing and costs.

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 6

Outcome Reporting in Cardiac Surgery Trials Goldfarb et al

ORIGINAL RESEARCH
when risks and benefits are both considered.46 Composite events are fundamentally different. Consider the difference
end points encompass postoperative complications, which are between medical versus surgical bleeding and ambulatory
important determinants of functional recovery and quality of versus perioperative troponin rise. The STS composite does not
life.47 Patient recruitment in cardiac surgery trials has include perioperative MI, which is in part due to its low
historically been difficult48 and continues to be challenging ascertainment reliability.1 Recommended definitions of peri-
despite the emergence of collaborative research networks.49 operative MI vary considerably, from a highly restrictive
Composite end points yield an increased number of events approach requiring evidence of an acute coronary embolus57
and a smaller required sample size, resulting in improved to a multifaceted approach incorporating clinical and biomar-
statistical efficiency and precision.50 This is especially true if ker criteria.55 Other potentially important cardiac surgery
event rates are low and efforts to analyze individual outcomes outcomes, such as prolonged postoperative mechanical ven-
or to perform meta-analyses lead to false-negative and false- tilation, have not been uniformly defined or adopted for use.
positive conclusions.51 Presenting a clear sample size calcu- VARC is a context-specific consensus document focused
lation matched to the primary outcome of interest, as was on transcatheter aortic valve replacement; it provides stan-
done in most reviewed trials, is critical in this regard. dardized end points with clearly defined criteria for reporting.5
Choosing the proper events to include in a cardiac A meta-analysis showed that the VARC end points were
surgery–specific composite end point is of vital importance. frequently being implemented to report clinical outcomes.58
The breadth of adverse events encountered after cardiac Although there has been an initial attempt to develop a similar
surgery is not captured by generic composite outcome document focused on pediatric cardiac surgery,59 there has
measures traditionally used in cardiology, such as MACE or yet to be an attempt in adult cardiac surgery.
MACCE. Acute kidney injury and deep sternal wound infec-
tions, for example, are postoperative events that are associ-
Limitations
ated with considerable morbidity. MI, the usual driver of
MACE-type end points in cardiology trials, has different Because our search was limited to 5 scientific journals (for
connotations and prognostic impact in the postoperative feasibility purposes), we did not capture trials published in
setting and concerns pertaining to measurement errors if other journals. The selected journals represent the highest
ascertaining MI soon after surgery. The use of composites ranked impact factors in their respective subspecialties of
may be justified only if each component is of similar cardiothoracic surgery, cardiology, and general medicine, and
importance to the patient,2 whereas it may be questionable we expect that the heterogeneity of outcome reporting could
if components are empirically different in impact (eg, deep have been more pronounced if we had included smaller lower
sternal wound infection and stroke).2 Assigning weights to the ranked studies. Conversely, the selected trials encompassed
components may circumvent this caveat and help increase a wide variety of interventions and comparators (surgery
the validity of conclusions.52 versus surgery, surgery versus transcatheter procedure,
Quality of life, physical performance, cognitive function, and surgery plus adjunctive medical therapy versus surgery alone),
dependency for activities of daily living have been broadly such that the heterogeneity of outcome reporting could have
categorized as patient-centered outcomes because they reflect been less pronounced if we restricted our selection criteria to
domains that are crucial to the patient but are extrinsic to one of these types of trials. We excluded trials that did not
traditional domains of mortality and pathophysiology that are report a clinically driven primary outcome, and this also led to
emphasized by physicians and researchers. There is increasing underrepresentation of smaller studies that were underpow-
awareness in the cardiovascular community that these data ered to assess clinical events. We chose to focus on clinical
should be collected and reported, particularly when studying events because these will likely form the basis of future
elderly populations in which the priority of care may have efforts to develop standardized guidelines for reporting
shifted from longevity to quality of life. Postoperative length of outcomes.
stay, stroke, and readmission have been identified as important
indicators of quality of care,53 strengthening the rationale for
also reporting these end points.54 Conclusion
For a criterion to be a useful part of a composite end point, it Outcome reporting in the cardiac surgery literature is
should be clinically important and reliably ascertainable. In the heterogeneous, and efforts should be made to standardize
cardiology literature, consensus efforts have been made to the outcomes reported and the definitions used to ascertain
standardize adjudication of MI,55,56 renal injury,3 and bleed- them. Measures of functional status and resource utilization
ing.4 These consensus documents are not necessarily portable are currently underreported and should be integrated in
to the specific context of cardiac surgery, for which the standardized reporting schema. The development of stan-
mechanism, magnitude, and clinical implication of certain dardizing outcome reporting is an essential step toward

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 7

Outcome Reporting in Cardiac Surgery Trials Goldfarb et al

ORIGINAL RESEARCH
strengthening the process of evidence-based care in cardiac 15. Kamalesh M, Sharp TG, Tang XC, Shunk K, Ward HB, Walsh J, King S III, Colling
C, Moritz T, Stroupe K, Reda D; Investigators VC. Percutaneous coronary
surgery. intervention versus coronary bypass surgery in United States veterans with
diabetes. J Am Coll Cardiol. 2013;61:808–816.
16. Karkouti K, von Heymann C, Jespersen CM, Korte W, Levy JH, Ranucci M,
Sellke FW, Song HK. Efficacy and safety of recombinant factor XIII on reducing
blood transfusions in cardiac surgery: a randomized, placebo-controlled,
Sources of Funding multicenter clinical trial. J Thorac Cardiovasc Surg. 2013;146:927–939.
Dr Afilalo is supported by a Research Scholar award from the 17. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E, Straka Z,
Piegas LS, Akar AR, Jain AR, Noiseux N, Padmanabhan C, Bahamondes JC,
FRQ-S. Novick RJ, Vaijyanath P, Reddy SK, Tao L, Olavegogeascoechea PA, Airan B,
Sulling TA, Whitlock RP, Ou Y, Pogue J, Chrolavicius S, Yusuf S; Investigators C.
Effects of off-pump and on-pump coronary-artery bypass grafting at 1 year.
N Engl J Med. 2013;368:1179–1188.
Disclosures 18. Sezai A, Nakata K, Iida M, Yoshitake I, Wakui S, Hata H, Shiono M. Results of
low-dose carperitide infusion in high-risk patients undergoing coronary artery
None. bypass grafting. Ann Thorac Surg. 2013;96:119–126.
19. Shi J, Wang G, Lv H, Yuan S, Wang Y, Ji H, Li L. Tranexamic acid in on-pump
coronary artery bypass grafting without clopidogrel and aspirin cessation:
randomized trial and 1-year follow-up. Ann Thorac Surg. 2013;95:795–802.
References 20. Bokesch PM, Szabo G, Wojdyga R, Grocott HP, Smith PK, Mazer CD,
1. Shahian DM, O’Brien SM, Filardo G, Ferraris VA, Haan CK, Rich JB, Normand Vetticaden S, Wheeler A, Levy JH. A phase 2 prospective, randomized, double-
SL, DeLong ER, Shewan CM, Dokholyan RS, Peterson ED, Edwards FH, blind trial comparing the effects of tranexamic acid with ecallantide on blood
Anderson RP; Society of Thoracic Surgeons Quality Measurement Task F. The loss from high-risk cardiac surgery with cardiopulmonary bypass (CONSERV-2
society of thoracic surgeons 2008 cardiac surgery risk models: part 1– trial). J Thorac Cardiovasc Surg. 2012;143:1022–1029.
coronary artery bypass grafting surgery. Ann Thorac Surg. 2009;88:S2–S22.
21. Deja MA, Kargul T, Domaradzki W, Stacel T, Mazur W, Wojakowski W, Gocol R,
2. Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in Gaszewska-Zurek E, Zurek P, Pytel A, Wos S. Effects of preoperative aspirin in
randomized trials: greater precision but with greater uncertainty? JAMA. coronary artery bypass grafting: a double-blind, placebo-controlled, random-
2003;289:2554–2559. ized trial. J Thorac Cardiovasc Surg. 2012;144:204–209.
3. Lopes JA, Jorge S. The RIFLE and AKIN classifications for acute kidney injury: a 22. Desai SP, Henry LL, Holmes SD, Hunt SL, Martin CT, Hebsur S, Ad N. Strict
critical and comprehensive review. Clin Kidney J. 2013;6:8–14. versus liberal target range for perioperative glucose in patients undergoing
4. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, coronary artery bypass grafting: a prospective randomized controlled trial.
Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, J Thorac Cardiovasc Surg. 2012;143:318–325.
Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. 23. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, Yang M,
Standardized bleeding definitions for cardiovascular clinical trials: a consensus Cohen DJ, Rosenberg Y, Solomon SD, Desai AS, Gersh BJ, Magnuson EA,
report from the bleeding academic research consortium. Circulation. Lansky A, Boineau R, Weinberger J, Ramanathan K, Sousa JE, Rankin J,
2011;123:2736–2747. Bhargava B, Buse J, Hueb W, Smith CR, Muratov V, Bansilal S, King S III,
5. Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone Bertrand M, Fuster V; Investigators FT. Strategies for multivessel revascular-
EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, ization in patients with diabetes. N Engl J Med. 2012;367:2375–2384.
Kodali S, Mack MJ, Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker
24. Houlind K, Kjeldsen BJ, Madsen SN, Rasmussen BS, Holme SJ, Nielsen PH,
S, Serruys PW, Leon MB; Valve Academic Research C. Updated standardized
Mortensen PE; Group DS. On-pump versus off-pump coronary artery bypass
endpoint definitions for transcatheter aortic valve implantation: the valve
surgery in elderly patients: results from the Danish on-pump versus off-pump
academic research consortium-2 consensus document. J Thorac Cardiovasc
randomization study. Circulation. 2012;125:2431–2439.
Surg. 2013;145:6–23.
25. Kang DH, Kim YJ, Kim SH, Sun BJ, Kim DH, Yun SC, Song JM, Choo SJ, Chung
6. Citefactor. Impact factor list 2014. Available at: http://www.citefactor.org/
CH, Song JK, Lee JW, Sohn DW. Early surgery versus conventional treatment
journal-impact-factor-list-2014_C.html. Accessed January 5, 2015.
for infective endocarditis. N Engl J Med. 2012;366:2466–2473.
7. Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with
composite end points in cardiovascular studies: the story of major adverse 26. Lemma MG, Coscioni E, Tritto FP, Centofanti P, Fondacone C, Salica A, Rossi A,
cardiac events and percutaneous coronary intervention. J Am Coll Cardiol. De Santo T, Di Benedetto G, Piazza L, Rinaldi M, Schinosa AL, De Paulis R,
2008;51:701–707. Contino M, Genoni M. On-pump versus off-pump coronary artery bypass surgery
in high-risk patients: operative results of a prospective randomized trial (on-off
8. Pilcher JM, Young P, Weatherall M, Rahman I, Bonser RS, Beasley RW. A study). J Thorac Cardiovasc Surg. 2012;143:625–631.
systematic review and meta-analysis of the cardioprotective effects of remote
ischaemic preconditioning in open cardiac surgery. J R Soc Med. 27. Mannacio V, Di Tommaso L, De Amicis V, Stassano P, Musumeci F, Vosa C.
2012;105:436–445. Preoperative intraaortic balloon pump for off-pump coronary arterial revascu-
larization. Ann Thorac Surg. 2012;93:804–809.
9. Farrokhyar F, Karanicolas PJ, Thoma A, Simunovic M, Bhandari M, Devereaux
PJ, Anvari M, Adili A, Guyatt G. Randomized controlled trials of surgical 28. Sezai A, Nakai T, Hata M, Yoshitake I, Shiono M, Kunimoto S, Hirayama A.
interventions. Ann Surg. 2010;251:409–416. Feasibility of landiolol and bisoprolol for prevention of atrial fibrillation after
coronary artery bypass grafting: a pilot study. J Thorac Cardiovasc Surg.
10. Guru V, Anderson GM, Fremes SE, O’Connor GT, Grover FL, Tu JV; Canadian 2012;144:1241–1248.
CSQICP. The identification and development of Canadian coronary artery
bypass graft surgery quality indicators. J Thorac Cardiovasc Surg. 29. Torina AG, Silveira-Filho LM, Vilarinho KA, Eghtesady P, Oliveira PP, Sposito
2005;130:1257. AC, Petrucci O. Use of modified ultrafiltration in adults undergoing coronary
artery bypass grafting is associated with inflammatory modulation and less
11. Adams DH, Popma JJ, Reardon MJ. Transcatheter aortic-valve replacement with postoperative blood loss: a randomized and controlled study. J Thorac
a self-expanding prosthesis. N Engl J Med. 2014;371:967–968. Cardiovasc Surg. 2012;144:663–670.
12. Morice MC, Serruys PW, Kappetein AP, Feldman TE, Stahle E, Colombo A, 30. Bonow RO, Maurer G, Lee KL, Holly TA, Binkley PF, Desvigne-Nickens P,
Mack MJ, Holmes DR, Choi JW, Ruzyllo W, Religa G, Huang J, Roy K, Dawkins Drozdz J, Farsky PS, Feldman AM, Doenst T, Michler RE, Berman DS, Nicolau
KD, Mohr F. Five-year outcomes in patients with left main disease treated with JC, Pellikka PA, Wrobel K, Alotti N, Asch FM, Favaloro LE, She L, Velazquez EJ,
either percutaneous coronary intervention or coronary artery bypass grafting Jones RH, Panza JA; Investigators ST. Myocardial viability and survival in
in the synergy between percutaneous coronary intervention with taxus and ischemic left ventricular dysfunction. N Engl J Med. 2011;364:1617–1625.
cardiac surgery trial. Circulation. 2014;129:2388–2394.
31. Feldman T, Foster E, Glower DD, Kar S, Rinaldi MJ, Fail PS, Smalling RW, Siegel
13. Chocron S, Vandel P, Durst C, Laluc F, Kaili D, Chocron M, Etievent JP. R, Rose GA, Engeron E, Loghin C, Trento A, Skipper ER, Fudge T, Letsou GV,
Antidepressant therapy in patients undergoing coronary artery bypass Massaro JM, Mauri L; Investigators EI. Percutaneous repair or surgery for
grafting: the MOTIV-CABG trial. Ann Thorac Surg. 2013;95:1609–1618. mitral regurgitation. N Engl J Med. 2011;364:1395–1406.
14. Diegeler A, Borgermann J, Kappert U, Breuer M, Boning A, Ursulescu A, Rastan A, 32. Kourliouros A, Valencia O, Hosseini MT, Mayr M, Sarsam M, Camm J, Jahangiri
Holzhey D, Treede H, Riess FC, Veeckmann P, Asfoor A, Reents W, Zacher M, M. Preoperative high-dose atorvastatin for prevention of atrial fibrillation after
Hilker M; Group GS. Off-pump versus on-pump coronary-artery bypass grafting cardiac surgery: a randomized controlled trial. J Thorac Cardiovasc Surg.
in elderly patients. N Engl J Med. 2013;368:1189–1198. 2011;141:244–248.

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 8

Outcome Reporting in Cardiac Surgery Trials Goldfarb et al

ORIGINAL RESEARCH
33. Mehta RH, Ferguson TB, Lopes RD, Hafley GE, Mack MJ, Kouchoukos NT, 47. Herman CR, Buth KJ, Legare JF, Levy AR, Baskett R. Development of a
Gibson CM, Harrington RA, Califf RM, Peterson ED, Alexander JH. Saphenous predictive model for major adverse cardiac events in a coronary artery bypass
vein grafts with multiple versus single distal targets in patients undergoing and valve population. J Cardiothorac Surg. 2013;8:177.
coronary artery bypass surgery: one-year graft failure and five-year outcomes 48. Gardner TJ, O’Gara PT. The cardiothoracic surgery network: randomized clinical
from the project of ex-vivo vein graft engineering via transfection (PREVENT) IV trials in the operating room. J Thorac Cardiovasc Surg. 2010;139:830–834.
trial. Circulation. 2011;124:280–288.
49. Dieleman JM, Nierich AP, Rosseel PM, van der Maaten JM, Hofland J, Diephuis
34. Sezai A, Hata M, Niino T, Yoshitake I, Unosawa S, Wakui S, Kimura H, Shiono JC, Schepp RM, Boer C, Moons KG, van Herwerden LA, Tijssen JG, Numan SC,
M, Takayama T, Hirayama A. Results of low-dose human atrial natriuretic Kalkman CJ, van Dijk D; Dexamethasone for Cardiac Surgery Study G.
peptide infusion in nondialysis patients with chronic kidney disease undergo- Intraoperative high-dose dexamethasone for cardiac surgery: a randomized
ing coronary artery bypass grafting: the NU-HIT (Nihon University working controlled trial. JAMA. 2012;308:1761–1767.
group study of low-dose HANP infusion therapy during cardiac surgery) trial for
CKD. J Am Coll Cardiol. 2011;58:897–903. 50. Novitzky D, Shroyer AL, Collins JF, McDonald GO, Lucke J, Hattler B, Kozora E,
Bradham DD, Baltz J, Grover FL; Group VAROOBS. A study design to assess the
35. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, safety and efficacy of on-pump versus off-pump coronary bypass grafting: the
Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, ROOBY trial. Clin Trials. 2007;4:81–91.
Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC,
Akin JJ, Anderson WN, Wang D, Pocock SJ. Transcatheter versus surgical 51. Guyatt G, Devereaux PJ, Yusuf S, Yang H, Alonso-Coello P, Ciapponi A, Pogue J,
aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364: Salazar A, Tristan M, Urrutia G. Small sample size, composite endpoints, trials
2187–2198. stopped early for benefit: threats to valid meta-analysis. Oral presentation at
the 16th Cochrane Colloquium: evidence in the era of globalisation. Z Evid
36. Wimmer-Greinecker G, Bouchot O, Verhoye JP, Perrault LP, Borgermann J, Fortbild Qual Gesundhwes. 2008;102(suppl VI):31.
Diegeler A, Van Garsse L, Rastan AJ. Randomized clinical trial comparing a
thermosensitive polymer (LeGoo) with conventional vessel loops for temporary 52. Tong BC, Huber JC, Ascheim DD, Puskas JD, Ferguson TB Jr, Blackstone EH,
coronary artery occlusion during off-pump coronary artery bypass surgery. Ann Smith PK. Weighting composite endpoints in clinical trials: essential evidence
Thorac Surg. 2011;92:2177–2183. for the heart team. Ann Thorac Surg. 2012;94:1908–1913.
37. Grossi EA, Patel N, Woo YJ, Goldberg JD, Schwartz CF, Subramanian V, 53. Liao YC, Lin YJ, Chung FP, Chang SL, Lo LW, Hu YF, Chao TF, Chung E, Tuan TC,
Feldman T, Bourge R, Baumgartner N, Genco C, Goldman S, Zenati M, Huang JL, Liao JN, Chen YY, Chen SA. Risk stratification of arrhythmogenic
Wolfe JA, Mishra YK, Trehan N, Mittal S, Shang S, Mortier TJ, Schweich CJ right ventricular cardiomyopathy based on signal averaged electrocardio-
Jr. Outcomes of the RESTOR-MV trial (randomized evaluation of a surgical grams. Int J Cardiol. 2014;174:628–633.
treatment for off-pump repair of the mitral valve). J Am Coll Cardiol. 54. Ferreira-Gonzalez I, Permanyer-Miralda G, Busse JW, Devereaux PJ, Guyatt GH,
2010;56:1984–1993. Alonso-Coello P, Montori VM. Composite outcomes can distort the nature and
38. Hueb W, Lopes N, Gersh BJ, Soares PR, Ribeiro EE, Pereira AC, Favarato D, magnitude of treatment benefits in clinical trials. Ann Intern Med.
Rocha AS, Hueb AC, Ramires JA. Ten-year follow-up survival of the medicine, 2009;150:566–567.
angioplasty, or surgery study (MASS II): a randomized controlled clinical trial of 55. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; Joint ESC/
3 therapeutic strategies for multivessel coronary artery disease. Circulation. AHA/WHF Authors/Task Force Members C, Thygesen K, Alpert JS, White HD;
2010;122:949–957. Biomarker S, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA; Subcommittee
39. Hueb W, Lopes NH, Pereira AC, Hueb AC, Soares PR, Favarato D, Vieira RD, ECG, Chaitman BR, Clemmensen PM, Johanson P, Hod H; Imaging S, Underwood
Lima EG, Garzillo CL, Paulitch Fda S, Cesar LA, Gersh BJ, Ramires JA. Five-year R, Bax JJ, Bonow JJ, Pinto F, Gibbons RJ; Classification S, Fox KA, Atar D, Newby
follow-up of a randomized comparison between off-pump and on-pump stable LK, Galvani M, Hamm CW; Intervention S, Uretsky BF, Steg PG, Wijns W, Bassand
multivessel coronary artery bypass grafting. The MASS III Trial. Circulation. JP, Menasche P, Ravkilde J; Trials, Registries S, Ohman EM, Antman EM, Wallentin
2010;122:S48–52. LC, Armstrong PW, Simoons ML; Trials, Registries S, Januzzi JL, Nieminen MS,
Gheorghiade M, Filippatos G; Trials, Registries S, Luepker RV, Fortmann SP,
40. Kapur A, Hall RJ, Malik IS, Qureshi AC, Butts J, de Belder M, Baumbach A, Rosamond WD, Levy D, Wood D; Trials, Registries S, Smith SC, Hu D, Lopez-
Angelini G, de Belder A, Oldroyd KG, Flather M, Roughton M, Nihoyannopoulos P, Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN,
Bagger JP, Morgan K, Beatt KJ. Randomized comparison of percutaneous Vasilieva EJ, Mendis S; Guidelines ESCCfP, Bax JJ, Baumgartner H, Ceconi C,
coronary intervention with coronary artery bypass grafting in diabetic patients. Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P,
1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes
trial. J Am Coll Cardiol. 2010;55:432–440. PA, Tendera M, Torbicki A, Vahanian A, Windecker S; Document R, Morais J,
41. Moller CH, Perko MJ, Lund JT, Andersen LW, Kelbaek H, Madsen JK, Winkel Aguiar C, Almahmeed W, Arnar DO, Barili F, Bloch KD, Bolger AF, Botker HE,
P, Gluud C, Steinbruchel DA. No major differences in 30-day outcomes in Bozkurt B, Bugiardini R, Cannon C, de Lemos J, Eberli FR, Escobar E, Hlatky M,
high-risk patients randomized to off-pump versus on-pump coronary James S, Kern KB, Moliterno DJ, Mueller C, Neskovic AN, Pieske BM, Schulman
bypass surgery: the Best Bypass Surgery Trial. Circulation. 2010;121: SP, Storey RF, Taubert KA, Vranckx P, Wagner DR. Third universal definition of
498–504. myocardial infarction. J Am Coll Cardiol. 2012;60:1581–1598.
56. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow GC,
42. Omran AS, Karimi A, Ahmadi H, Yazdanifard P, Sheikh Fahtollahi M, Tazik M.
Jacobs JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW, Mehran R, Nissen
Prophylactic ventral cardiac denervation: does it reduce incidence of atrial SE, Smith EE, Targum SL. 2014 ACC/AHA key data elements and definitions
fibrillation after coronary artery bypass grafting? J Thorac Cardiovasc Surg.
for cardiovascular endpoint events in clinical trials: a report of the American
2010;140:1036–1039. College of Cardiology/American Heart Association task force on clinical data
43. Veeger NJ, Zijlstra F, Hillege HL, van der Meer J. Fourteen-year follow-up from standards (writing committee to develop cardiovascular endpoints data
cabadas: vitamin K antagonists or dipyridamole not superior to aspirin. Ann standards). J Am Coll Cardiol. 2014;66:403–469.
Thorac Surg. 2010;90:1515–1521.
57. Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier GL,
44. Weltert L, D’Alessandro S, Nardella S, Girola F, Bellisario A, Maselli D, De Takkenberg JJ, David TE, Butchart EG, Adams DH, Shahian DM, Hagl S, Mayer JE,
Paulis R. Preoperative very short-term, high-dose erythropoietin administration Lytle BW; STS, AATS, EACTS. Guidelines for reporting mortality and morbidity
diminishes blood transfusion rate in off-pump coronary artery bypass: a after cardiac valve interventions. Ann Thorac Surg. 2008;85:1490–1495.
randomized blind controlled study. J Thorac Cardiovasc Surg. 2010;139: 58. Genereux P, Head SJ, Van Mieghem NM, Kodali S, Kirtane AJ, Xu K, Smith C,
621–626; discussion 626-627.
Serruys PW, Kappetein AP, Leon MB. Clinical outcomes after transcatheter
45. Lim E, Brown A, Helmy A, Mussa S, Altman DG. Composite outcomes in aortic valve replacement using valve academic research consortium defini-
cardiovascular research: a survey of randomized trials. Ann Intern Med. tions: a weighted meta-analysis of 3,519 patients from 16 studies. J Am Coll
2008;149:612–617. Cardiol. 2012;59:2317–2326.
46. Ferreira-Gonzalez I, Alonso-Coello P, Sola I, Pacheco-Huergo V, Domingo- 59. Butts RJ, Scheurer MA, Zyblewski SC, Wahlquist AE, Nietert PJ, Bradley SM, Atz
Salvany A, Alonso J, Montori V, Permanyer-Miralda G. Composite endpoints in AM, Graham EM. A composite outcome for neonatal cardiac surgery research.
clinical trials. Rev Esp Cardiol. 2008;61:283–290. J Thorac Cardiovasc Surg. 2014;147:428–433.

DOI: 10.1161/JAHA.115.002204 Journal of the American Heart Association 9